The flow of blood is regulated by opposing biochemical pathways. A key example is the coagulation pathway, which produces a fibrin clot to seal vascular leaks, and the opposing fibrinolysis pathway, which subsequently dissolves the clot to ensure normal blood flow is restored. Thrombosis is the disease that results when balance is lost and clotting occurs where it should not. By understanding the molecules involved in maintaining blood flow, drugs have been developed that quickly dissolve these thrombi and reduce the tissue damage caused by oxygen deprivation, especially in acute myocardial infarction. The “clot busters” that have had the greatest impact and are under most intense development are analogues of the natural protein, tissue plasminogen activator (tPA), which is an important initiator of fibrinolysis. However, tPA is not a perfect drug, because it is an active enzyme. Its activity not only helps dissolve the target clot, but systemic rather than strictly localized effects also deplete blood of essential coagulation proteins. This is dangerous because administration of the current thrombolytic drugs often leads to haemorrhage. To avoid some of the complications associated with tPA, novel strategies to better initiate clot lysis are required.